Nasal foam via cribriform plate for medication delivery to the brain and/or body and for nasal moisturization and hygiene

ABSTRACT

Methods and compositions for delivering medicine and other substances to the brain and the body via the cribriform plate using foamable compositions are described. Methods and compositions for improving nasal hygiene and moisturizing the nasal cavity using foamable compositions are also described.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. patentapplication Ser. No. 15/205,611, filed Jul. 8, 2016, which claims thebenefit of U.S. Provisional Patent Application No. 62/191,147, filedJul. 10, 2015 and U.S. Provisional Patent Application No. 62/269,348,filed Dec. 18, 2015, the entire disclosures of which are herebyincorporated by reference herein.

BACKGROUND OF THE INVENTION

Delivering medications and other substances to the brain is verydesirable for CNS active drugs but extremely challenging. Even if amedication is injected into the bloodstream, e.g., intravenously, it maynot cross the barrier between blood and brain called the blood brainbarrier. Also, many medications can be destroyed by blood and thuspreferred to be given directly to the brain. Giving the medications viathe oral route creates a further barrier of absorption and metabolism bystomach gut and liver, before the medications reach the blood. So allthese methods reduce the percentage of actual medication that will reachthe brain if at all and also slows the time of action. This leads totaking an extra dose of medication for the same results, which in turncauses an increase in side effect profile.

A mechanism of direct brain delivery via cribriform plate, thusbypassing the blood brain barrier, gut and liver is desirable. Thecribriform plate is a porous plate of bone located between brain andnose in the roof of nasal cavity that has holes through which nerves andblood vessels pass through between nose and brain. Medications/chemicalsand substances can reach the brain from the nose through these sameholes. This allows for a larger percentage of an active substance to betransported to the brain or bloodstream at a much faster rate comparedto other modes of delivery, including intravenous, oral or othermethods.

The way to reach the cribriform plate is via the nasal cavity. Currentmodes of medication or substance delivery through the nasal cavityinclude nasal sprays, mists, aerosols, and liquid and gel formulations.One problem with current modes of nasal delivery is that they are unableto reach the back part of the roof of the nasal cavity, where thecribriform plate is located. Another problem is that the contact periodof such substances with the nasal cavity is minimal, and therefore thetime period for transport, i.e., absorption into the bloodstream orbrain, is decreased. This leads to less absorption of the drug in thenasal cavity or body and substantially reduced efficacy of the drug. Itwould therefore be desirable to have a substance delivery method andcomposition that is able to fill the entire nasal cavity and reach theroof of the nasal cavity and that has a longer contact period with thenasal mucosa. Another problem with the liquid, spray and gel form isdripping into the throat that not only wastes medicine and drugs but isuncomfortable to the patient and can cause choking.

BRIEF SUMMARY OF THE INVENTION

The disclosed embodiments are generally directed to methods andcompositions for delivering medicine and other substances to the brainvia the cribriform plate located in the back part of the roof of thenose (or olfactory part of the nasal cavity) using foam compositions.These methods and compositions can also be used to deliver drugs to therest of the body besides the brain and for improving nasal hygiene andmoisturization using foam compositions. These methods and compositionscan also be used for local nasal and sinus applications for variouschemicals/medications/substances.

The foam composition may comprise a base solution along with apropellant gas or air. The base solution may be mixed with thepropellant gas or air at the time of delivery, prior to delivery orafter delivery to the target area. The base solution may include, forexample various compositions of water, salt, fat, milk, oil, proteinsand other substance or various combinations of some or all of theconstituents. It may also include the medicine, chemicals, stem cells,hormones, peptides or other substances to be delivered. Other additionsto this base solution formula may include various surfactants, foamingagents, stabilizing agents, pH modifying agents, osmolarity modifyingagents, moisturizing agents and preservatives. More modification can bedone by adding absorption enhancing agents and a variety of otheragents. All the substances or medicine in the base solution can be ofvarying sizes including nano particles of less than 1 nanometer to morethan 2000 nanometers.

The foaming agents can, be single or mixed product of severalsurfactants and may include, for example, various compositions of sodiumlauryl ether sulfate (SLES), sodium lauryl sulfate (also known as sodiumdodecyl sulfate or SDS) and ammonium lauryl sulfate (ALS). Nitrousoxide, air, CO₂ or other gaseous products may be used to create bubblesin the foam composition, allowing substances to fill the entire nasalcavity with an increased contact period. To make the foam after themedicine or substance has been delivered, the medicine or drugs can beapplied to the target area first in a powdered, dry or gas treated drypowder form and then the base solution can be propelled with gas or airto the target area forming the foam of the medicinal powder at thetarget area.

Moisturizing agents may include, for example, glycerin, aloe vera,hyaluronan, shea butter, milk fat, or oil, including but not limited toolive oil, coconut oil, flaxseed oil, avocado oil or almond oil.

In addition to a vehicle for medicine delivery to the brain via thecribriform plate or to the body via the nasal cavity, these methods mayalso be used to moisturize the nasal cavity or to clean the nasal cavityfor better hygiene, making it extremely useful for people working industy, dry, and polluted environments. At present, nasal hygiene methodsinclude sprays and liquid compositions, which have the problems ofreaching only a partial area of the nose, minimal contact time with thenasal cavity, dripping in the throat causing discomfort to the patientsand possible choking hazard. Although specific examples of novel foamcompositions are included herein, any foam composition may be used forthe nasal hygiene improvement, and nasal moisturization methodsdescribed.

In one embodiment, a method of delivering a foamable pharmaceuticalcomposition to the cribriform plate of a nasal cavity of a subject isprovided comprising generating a biologically active foam compositionsufficient to deliver at least 50% of an active agent across a bloodbrain barrier of the subject and delivering the biologically activeagent foam composition to the cribriform plate of the nasal cavity,wherein the biologically active foam composition comprises an activeagent selected from the group consisting of a stem cell, anantimicrobial agent, an antineoplastic agent, an antiarrhythmic agent,an antihypertensive agent, an analgesic agent, anti-inflammatory agent,an anticonvulsant, an anti-Parkinson's agent, a sedative, a musclerelaxant, an anticoagulant, a hormone modulator, an immunosuppressiveagent, a metabolic agent, an anesthetic, a nutritional supplement, anantidepressant, a radiologic agent, and an antimigraine agent, and astabilizing agent.

In another embodiment, a method for delivering a foamable salinesolution for cleansing and hydrating the nasal cavity is provided.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The foregoing summary as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings. For the purpose of illustrating the invention,there are shown in the drawings embodiments which are presentlypreferred. It should be understood, however, that the invention is notlimited to the precise arrangements and instrumentalities shown.

In the drawings:

FIG. 1 illustrates an example of a foam composition in accordance withan aspect of the present invention in a magnified view;

FIG. 2 illustrates a cross-sectional view of nose including the locationof the cribriform plate in the roof of the nose;

FIG. 3 illustrates a schematic cross-sectional view of an exemplarydevice to deliver foam to the nasal cavity in accordance with an aspectof the present invention; and

FIGS. 4A-4C illustrate an exemplary use device in accordance with anaspect of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to the present embodiments of theinvention illustrated in the accompanying drawings. Wherever possible,the same or like reference numbers will be used throughout the drawingsto refer to the same or like features. It should be noted that thedrawings are in simplified form and are not drawn to precise scale. Inreference to the disclosure herein, for purposes of convenience andclarity only, directional terms such as top, bottom, above, below anddiagonal, are used with respect to the accompanying drawings. Suchdirectional terms used in conjunction with the following description ofthe drawings should not be construed to limit the scope of the inventionin any manner not explicitly set forth.

Certain terminology is used in the following description for convenienceonly and is not limiting. The words “right,” “left,” “lower” and “upper”designate directions in the drawings to which reference is made. Thewords “inwardly” and “outwardly” refer to directions toward and awayfrom, respectively, the geometric center of the identified element anddesignated parts thereof. Additionally, the term “a,” a used in thespecification, means “at least one.” The terminology includes the wordsnoted above, derivatives thereof and words of similar import.

“About” as used herein when referring to a measurable value such as anamount, a temporal duration, and the like, is meant to encompassvariations of ±20%, ±10%, ±5%, ±1%, and ±0.1% from the specified value,as such variations are appropriate.

Ranges: throughout this disclosure, various aspects of the invention canbe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. Thisapplies regardless of the breadth of the range.

“Active agent” as used herein refers to any medication or substancehaving a therapeutic effect on a subject.

As used herein, the terms “foam” and “foam composition” are meant toencompass complete and petal foam compositions.

Furthermore, the described features, advantages and characteristics ofthe embodiments of the invention may be combined in any suitable mannerin one or more embodiments. One skilled in the relevant art willrecognize, in light of the description herein, that the invention can bepracticed without one or more of the specific features or advantages ofa particular embodiment. In other instances, additional features andadvantages may be recognized in certain embodiments that may not bepresent in all embodiments of the invention.

FIG. 1 illustrates an example of a foam composition 100 in magnifiedview, in which one or more disclosed embodiments may be implemented. Inone embodiment, the foam composition 100 comprises an active agent 10,i.e. medicine or other substance and a gas 20. The foam composition 100may deliver the active agent 10, to the brain or body via the cribriformplate area of the nose.

FIG. 2 shows the roof of the nasal cavity formed by the cribriform plate201, nasal bones 202, nasal spine of the frontal bone 203, vomer 204,opening of the sphenoidal sinus 205, ala of vormer 206 and sphenoidalrostrum 207.

Any medication or chemical substance can be delivered through the nasalmucosa, including the ones whose target and function are directly in thebrain, as the cribriform plate area provides a direct route to the brainwithout passing through the gut, liver, or blood brain barrier. Suchmedications may include but are not limited to several lifesavingmedications e.g., those used to treat seizures, drug overdose oraddiction, e.g., naloxone, buprenorphine and midazolam, headache andmigraine, e.g., triptans, excessive sedation, e.g. caffeine or nicotine,depression, and brain tumors, pain medications, vaccines, stem cells,hormones like glucagon, insulin and oxytocin, and Alzheimer's disease,e.g., insulin, nicotine, and vitamins.

Examples of an active agent include but are not limited to: a stem cell,a genetically modified stem cell, an anti-infective, an amebicide, anaminoglycoside, an anthelmintic, an antifungal, an azole antifungal, anechinocandin, a polyene, an antimalarial agent, an antimalarialquinolone, an antituberculosis agent, an aminosalicylate, adiarylquinoline, a hydrazide derivative, a nicotinic acid derivative, arifamycin derivative, a Streptomyces derivative, an antiviral agent, anadamantane antiviral, an antiviral booster, an antiviral interferon, achemokine receptor an antagonist, an integrase strand transferinhibitor, a neuraminidase inhibitor, a NNRTI, a NS5A inhibitors, anucleoside reverse transcriptase inhibitor (NRTI), a protease inhibitor,a purine nucleoside, a carbapenem, a cephalosporin, acephalosporin/beta-lactamase inhibitor, a first generationcephalosporin, a fourth generation cephalosporin, a next generationcephalosporin, a second generation cephalosporin, a third generationcephalosporin, a glycopeptide antibiotics, a glycylcycline, aleprostatic, a lincomycin derivative, a macrolide derivative, aketelide, a macrolide, an oxazolidinone antibiotic, a penicillin, anaminopenicillin, a antipseudomonal penicillin, a beta-lactamaseinhibitors, a natural penicillin, a penicillinase resistant penicillin,a quinolone, a sulfonamide, a tetracycline, a urinary anti-infective, anantineoplastic, are alkylating agent, an anti-CTLA-4 monoclonalantibody, an antibiotic/antineoplastic, an antimetabolite, anantineoplastic detoxifying agent, an antineoplastic interferon, aBCR-ABL tyrosine kinase inhibitor, a CD20 monoclonal antibody, a CD30monoclonal antibody, a CD33 monoclonal antibody, a CD38 monoclonalantibody, a CD52 monoclonal antibody, an EGFR inhibitor, a hedgehogpathway inhibitor, a HER2 inhibitor, a histone deacetylase inhibitor, ahormone/antineoplastic, an mitotic inhibitor, an mTOR inhibitor, amultikinase inhibitor, a proteasome inhibitor, a VEGF/VEGFR inhibitor, abiological, an antitoxin, are antivenom, a hematopoietic stem cellmobilizer, an in vivo diagnostic biological, a recombinant humanerythropoietin, a cardiovascular agent, an agent for hypertensiveemergencies, an agent for pulmonary hypertension, an aldosteronereceptor antagonist, an angiotensin a converting enzyme inhibitor, anangiotensin receptor blocker, a neprilysin inhibitor, an antiadrenergicagent, a centrally acting antiadrenergic agent, a peripherally actingagent, an antianginal agent, an antiarrhythmic agent, a group Iantiarrhythmic, a group II antiarrhythmic, a group III antiarrhythmic, agroup IV antiarrhythmic, a group V antiarrhythmic, an anticholinargicchronotropic agent, an antihypertensive agent, an ACE inhibitor withcalcium channel blocking agents, an ACE inhibitor with a thiazide, anangiotensin II inhibitor with calcium channel blockers, an angiotensinII inhibitor with a thiazide, an antiadrenergic agent (central) with athiazide, an antiadrenergic agent (peripheral) with a thiazide, a betablocker with a thiazide, a potassium sparing diuretic with a thiazide, abeta-adrenergic blocking agent, a cardioselective beta blocker, anon-cardioselective beta blocker, a calcium channel blocking agent, acatecholamine, a diuretic, a carbonic anhydrase inhibitor, a loopdiuretic, a potassium-sparing diuretic, a thiazide diuretic, aninotropic agent, a peripheral vasodilator, a renin inhibitor, asclerosing agent, a vasodilator, a vasopressin antagonist, avasopressor, a central nervous system agent, an analgesic, anantimigraine agent, a cox-2 inhibitor, a narcotic analgesic, anonsteroidal anti-inflammatory agent, a salicylate, an anorexiant, ananticonvulsant, an AMPA receptor antagonist, an barbiturateanticonvulsant, a benzodiazepine anticonvulsant, a carbamateanticonvulsant, a carbonic anhydrase inhibitor anticonvulsant, adibenzazepine anticonvulsant, a fatty acid derivative anticonvulsant, agamma-aminobutyric acid analog, a gamma-aminobutyric acid reuptakeinhibitor, a hydantoin anticonvulsant, a neuronal potassium channelopener, an oxazolidinedione anticonvulsant, a pyrrolidineanticonvulsant, an succinimide anticonvulsant, a triazineanticonvulsant, an antiemetic/antivertigo agent, a 5HT3 receptorantagonist, an anticholinergic antiemetic, a NK1 receptor antagonist, aphenothiazine antiemetic, an antiParkinson agent, an anticholinergicantiParkinson agent, a dopaminergic antiParkinsonism agent, ananxiolytic, a sedative, a hypnotic barbiturate, a benzodiazepine, asedative, a cholinergic agonist, a cholinesterase inhibitor, a CNSstimulant, drugs used in alcohol dependence, an anesthetic, a musclerelaxant, a neuromuscular blocking agent, a skeletal muscle relaxant, acoagulation modifier, an anticoagulant reversal agent, an anticoagulant,a coumarin, an indandione, a factor Xa inhibitor, a heparin, a thrombininhibitor, an antiplatelet agent, a glycoprotein platelet inhibitor, aplatelet aggregation inhibitor, protease-activated receptor-1antagonist, a heparin antagonist, a platelet-stimulating agent, athrombolytic, a hormone, a 5-alpha-reductase inhibitor, an adrenalcorticosteroid, a corticotropin, a glucocorticoid, a mineralocorticoid,an adrenal corticosteroid inhibitor, an antiandrogen, an antidiuretichormone, an antigonadotropic agent, an antithyroid agent, art aromataseinhibitor, a calcitonin, an estrogen receptor antagonist, agonadotropin-releasing hormone antagonist, a growth hormone receptorblocker, a growth hormone, an insulin-like growth factor, a parathyroidhormone and analog, a progesterone receptor modulator, a prolactininhibitor, a selective estrogen receptor modulator, a sex hormone, anandrogen, an anabolic steroid, a contraceptive, an estrogen, agonadotropin releasing hormone, a gonadotropin, a progestin, asomatostatin, a somatostatin analog, a synthetic ovulation stimulant, athyroid drug, an immunologic agent, an immune globulin, animmunostimulant, a bacterial vaccine, a colony stimulating factor, aninterferon, an interleukin, a therapeutic vaccine, a viral vaccine, animmunosuppressive agent, a calcineurin inhibitor, an interleukininhibitor, a TNF alfa inhibitor, a metabolic agent, an antidiabeticagent, an alpha-glucosidase inhibitor, an amylin analog, a dipeptidylpeptidase 4 inhibitor, an incretin mimetic, an insulin, a meglitinide, anon-sulfonylurea, a SGLT-2 inhibitor, a sulfonylurea, athiazolidinedione, an antihyperlipidemic agent, a bile add sequestrant,a cholesterol absorption inhibitor, a fibric acid derivative, a PCSK9inhibitor, a statin, an antihyperuricemic agent, a bone resorptioninhibitor, a bisphosphonate, a bone resorption inhibitor, a CFTR, a CFTRpotentiator, a glucose elevating agent, a lysosomal enzyme, amiscellaneous metabolic agent, a peripherally acting anti-obesity agent,a urea cycle disorder agent, an antidote, an antipsoriatic, anantirheumatic, a chelating agent, a cholinergic muscle stimulant, alocal anesthetic, including but not limited to ester-based andamide-based anesthetics, a phosphate binder, a psoralen, a smokingcessation agent, a viscosupplementation agent, a nutritional product, amineral, an electrolyte oral nutritional supplement, a plasma expander,a psychotherapeutic agent, an antidepressant, a monoamine oxidaseinhibitor, a phenylpiperazine antidepressant, a selective serotoninreuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, atetracyclic antidepressant, a tricyclic antidepressant, anantipsychotic, an atypical antipsychotic, a phenothiazine antipsychotic,a thioxanthene, a radiologic agent, a radiocontrast agent, an iodinatedcontrast media, an ionic iodinated contrast media, a lymphatic stainingagent, a magnetic resonance imaging contrast media, a diagnostic dye, anon-iodinated contrast media, a non-ionic iodinated contrast media, anultrasound contrast media, a radiologic adjunct, a cardiac stressingagent, a radiologic conjugating agent, a radiopharmaceutical, adiagnostic radiopharmaceutical, a therapeutic radiopharmaceutical, arespiratory agent, an antiasthmatic agent, an antihistamine, anantitussive, a methylxanthine, a decongestant, an expectorant, aleukotriene modifier, a lung surfactants, a respiratory agent, a mastcell stabilizer, a mucolytic, selective phosphodiesterase-4 inhibitor, amouth and throat product, a nasal preparation, a nasal antihistamine, adecongestant, a nasal lubricant, a nasal steroid, a vitamin, or a CNSactive medication, including but not limited to ketamine, glucagon,insulin, nicotine, caffeine, calcitonin, oxytocin, tetrahydrocannabinol(THC), cannabidiol (CBD), or natural cannabis, marijuana, cannabisderivatives or hemp oil, and an opioid or opioid derivative, orcombinations thereof.

In one embodiment, the active agent is naloxone, midazolam, ketamine,duloxetine, buprenorphine, morphine, a morphine derivative, fentanyl, afentanyl derivative, a triptan, a triptan derivative, methadone, amethadone derivative, lidocaine, tetracaine, cocaine, oxycodone, anoxycodone derivative, cisplatin, glucagon, insulin, nicotine, caffeine,ropinirole, calcitonin, oxytocin, a vitamin, tetrahydrocannabinol (THC),cannabidiol (CBD), cannabis, cannabis derivative, hemp oil, clonidine,gabapentin, pregabalin, cyclobenzapine, acetaminophen and acetaminophenderivatives, tramadol, tramadol derivatives, butalbital, butorphanol,meperidine, propoxyphene, levorphanol, nalbuphine, tapentadol orcombinations thereof.

The size of the particles can be reduced to nanoparticle size less than1 nanometer to greater than 2000 nanometers. The particles may beenclosed in liposomes. The foam composition may also be used to deliverstem cells to the brain via the nasal cavity. The foam composition 100may also enable better hygiene of the nasal cavity by the delivery ofboth moisturizing and cleaning substances.

The foam composition 100 may include a base solution and can be combinedwith a gas 20, for example nitrous oxide, or CO₂ or air. The resultingfoam composition, and as further discussed below, can be generated suchthat it is sufficient to deliver a desired amount of an active agente.g., sufficient to deliver at least 50% of an active agent across ablood brain barrier of the subject. The base solution may include themedicine or substance to be delivered and various compositions of water,fat, or other substance, for example, milk or saline, or a combinationof two or more.

Other additions to this base solution formula may include varioussurfactants, foaming agents, stabilizing agents, pH Modifying agents,osmolarity modifying agents, moisturizing agents and preservatives. Moremodification can be done by adding absorption enhancing agents andvariety of other modifying agents.

In one embodiment, the base solution may include the medicine or othersubstance and 1-99.999% water, by weight. In another example embodiment,the base solution may include the medicine or substance and 1-20% fat,by weight. In yet another example embodiment, the base solution mayinclude the medicine or substance 1-60% by weight. In yet anotherexample embodiment, the base solution may include the medicine orsubstance and a combination of 10-99% water, by weight and 30-60% fat,by weight. In yet another example embodiment, the base solution mayinclude the medicine or substance or stem cells and a combination of10-80% water, by weight and 20-60% other substance, by weight. In yetanother example embodiment, the base solution may include the medicineor substance or stem cells and a combination of 30-60% fat, by weightand 1-60% other substance/substances, by weight. In yet another exampleembodiment, the base solution may include the medicine or substance anda combination of 10-99.99% water, by weight, 0.1-60% modifying agentsincluding surfactant, foaming agents, stabilizing agents, osmolaritymodifying agents, drug absorption enhancer agents fat and 0.1-60% othersubstance/substances, by weight.

Stabilizing agents include, but are limited to xanthan gum, guar gum,and gelatin.

In one embodiment, the base solution may include the medicine or othersubstance and 10-80% water, by weight. In another embodiment, the basesolution may include the medicine or substance and 30-60% fat, byweight. In yet another embodiment, the base solution may include themedicine or substance and 20-60% milk, by weight. In yet anotherembodiment, the base solution may include the medicine or substance anda combination of 10-80% water, by weight and 30-60% fat, by weight. Inyet another embodiment, the base solution may include the medicine orsubstance and a combination of 10-80% water, by weight and 20-60% milk,by weight. In yet another embodiment, the base solution may include themedicine or substance and a combination of 30-60% fat, by weight, and20-60% milk, by weight. In yet another embodiment, the base solution mayinclude the medicine or substance and a combination of 10-80% water, byweight, 30-60% fat, by weight, and 20-60% milk, by weight.

The foaming agent may include several available agents. The foamingagents can be a single surfactant or mix of several surfactants and mayinclude, for example, various compositions of sodium lauryl ethersulfate (SLES), sodium lauryl sulfate (also known as sodium dodecylsulfate or SDS), ammonium lauryl sulfate (ALS), lecithin, glycerol,TWEEN 20 and TWEEN 80. The foam composition 100 may have an acidicneutral or alkaline pH. In addition, may be preferable that the foamcomposition be made of natural substances such as what has beendescribed; however, in alternative embodiments, mucosal-compatiblesynthetic substances may be used.

In one embodiment, the composition is aerated to form a foam by 1)dissolving a carbonate into the composition to form carbonate ions and2) dissolving a proton donor into the solution to release CO₂ gas andform the foam. The carbonate is may be sodium bicarbonate, calciumcarbonate, or potassium bicarbonate. The proton donor may be an acidselected from the group consisting of amino acids, carbonic acid, andacetic acid.

In one embodiment, the composition for cleansing or moisturizing a nasalcavity of a subject is a foamable saline solution. The saline solutionmay be a sterile, normal saline solution. In other embodiments, thesaline solution is hypertonic or hypotonic. The saline solution caninclude one or more other components such as a foaming agent, a pHmodifying agent, an osmolarity modifying agent, a stabilizing agent, amoisturizing agent, or a preservative.

In certain embodiments, at least 1%, at least 5%, at least 10%, at least20%, at least 30%, at least 40%, at least 50%, at least 60%, at least70%, at least 80% at least 90% or at least 95% of of the active agentcrosses the blood brain barrier. In one embodiment, the foamconpositions have a longer contact period with the nasal cavity comparedto the corresponding dry or liquid solutions.

FIG. 3 shows an embodiment of a device for delivering foam to thecribriform plate wherein the foam is produced within the device. In oneembodiment, the delivery device 301 comprises a composition chamber 303which can contain a biologically active composition or a salinesolution, a gas chamber 304, a composition inlet 305, a gas inlet 306, acomposition ejector 308, a gas ejector 309, a tube 310 and a foam outlet311. In one embodiment, the subject releases the composition using thecomposition ejector 308 and releases a jet of gas using the gas ejector309 which pushes the foam into the nose and directs it to the cribriformplate. In other embodiments, the foam and gas are premixed. The deliverydevice can be made of various materials such as metal, glass or plastic.The tube 310 can be bendable end the device can be held in anydirection.

The active agent can be delivered to the cribriform plate by sniffingthe foam composition, i.e., forceful inhalation. FIGS. 4A-4C illustratea subject using various foam delivery devices. FIG. 4A shows a deliverydevice 410 inserted in a nostril 401 wherein the person inhales throughthe nose, i.e., sniffs, to draw the foam from the foam inlet 401,through the tube 310 and through the foam outlet 311 such that the foamreaches the cribriform plate. In one embodiment, the foam substantiallyfills the nasal cavity. FIG. 4B shows a delivery device 420 inserted ina nostril 401 comprising a foam inlet 402, gas inlet 306, foam tube 310a, tube 310 and foam outlet 311. Foam can enter the device by variousmeans, for example, the foam inlet can be attached to a vesiclecontaining foam or a funnel through which foam is delivered. The gasinlet 308 can be attached to various means for delivering a gas,including but not limited to a gas canister, rubber bulb or syringe.FIG. 4C shows a delivery device 430 wherein the foam outlet 311 isinserted into a nostril 401 and the gas inlet 306 is inserted into thesubject's mouth so that the subject can exhale into the tube 310 andforce the foam from the foam inlet 402 through the tube 310 to the foamoutlet 311. The foam outlet 311 can have a rounded or bulbous ending forease of insertion and comfort of the subject.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. For example, additional components and stepscan be added to the various delivery devices or methods of delivery. Itis to be understood, therefore, that this invention is not limited tothe particular embodiments disclosed, but it is intended to covermodifications within the spirit and scope of the present invention asdefined by the appended claims.

I claim:
 1. A method for delivering a foam composition to a nasal cavityof a subject, comprising: a) applying a composition to a nasal cavity,the composition comprising: i) at least one active agent, ii) astabilizing agent; and iii) milk; b) aerating the composition to form afoam, and c) delivering the foam composition to the nasal cavity tosubstantially fill the nasal cavity.
 2. The method of claim 1, whereinthe composition contains sufficient active agent such that at least 60%of the active agent is delivered to the nasal cavity of the subject. 3.The method of claim 1, wherein the composition contains sufficientactive agent such that at least 70% of the active agent is delivered tothe nasal cavity of the subject.
 4. The method of claim 1, wherein theactive agent is dissolved or suspended in a solution comprising water,fat or saline or a combination thereof.
 5. The method of claim 4,wherein the solution comprises 10-80% water, by weight, and 30-60% fat,by weight.
 6. The method of claim 1, wherein the stabilizing agent is atleast one selected from the group consisting of xanthan gum, guar gum,and gelatin.
 7. The method of claim 1, further comprising a foamingagent selected from the group consisting of sodium lauryl sulfate,sodium lauryl ether sulfate, ammonium lauryl sulfate, lecithin,glycerol, TWEEN 20 and TWEEN
 80. 8. The method of claim 1, wherein thestep of aerating the composition to form a foam includes dispensing atleast one gas selected from the group consisting of air, N₂, N₂O, CO₂,HFC-134a and HFC-227ea.
 9. The method of claim 1, wherein the step ofaerating the composition to form a foam comprises the steps of: a)dissolving a carbonate into the composition to form carbonate ions, andb) dissolving a proton donor into the solution to release CO₂ gas. 10.The method of claim 9, wherein the carbonate is at least one selectedfrom the group consisting of sodium bicarbonate, calcium carbonate, andpotassium bicarbonate.
 11. The method of claim 9, wherein the protondonor is at least one acid selected from the group consisting of aminoacids, carbonic acid, and acetic acid.
 12. The method of claim 1,wherein the active agent is at least one selected from the groupconsisting of naloxone, midazolam, ketamine, duloxetine, buprenorphine,morphine, a morphine derivative, fentanyl, a fentanyl derivative, atriptan, a triptan derivative, methadone, a methadone derivative,lidocaine, tetracaine, cocaine, oxycodone, an oxycodone derivative,cisplatin, glucagon, insulin, nicotine, caffeine, ropinirole,calcitonin, oxytocin, a vitamin, tetrahydrocannabinol (THC), cannabidiol(CBD), cannabis, cannabis derivative, hemp oil, clonidine, gabapentin,pregabalin, cyclobenzapine, acetaminophen and acetaminophen derivatives,tramadol, tramadol derivatives, butalbital, butorphanol, meperidine,propoxyphene, levorphanol, nalbuphine, and tapentadol.